: The long-term objective of this proposal is to understand the molecular basis of the lethal neurodegenerative disease, amyotrophic lateral sclerosis (ALS). The principal investigator proposes to use familial cases of ALS as a tool to map, isolate and characterize genes which, when mutated, cause familial ALS. The rationale for continued application of genetics to ALS is that SOD1 mutations account for only a minority of familial ALS cases (ca 25 percent), strongly implying that additional ALS genes exist and cause the disease in the other 75 percent of familial ALS cases. Furthermore, such familial ALS genes may be involved in the manifestation of the more common sporadic form of ALS because of the high degree of similarity between the familial and sporadic forms of the disease. The Specific Aims are as follows: 1) identification and collection of ALS families where the cause of ALS is not due to mutations in the SOD1 gene; 2) use of the largest, non-SOD1 ALS families in a genome-wide search for ALS genes through genetic linkage analysis; 3) high resolution genetic mapping of additional ALS genes; 4) physical mapping of additional ALS genes; 5) mutational analysis of candidate ALS genes. Identification of additional ALS genes will permit genetic testing useful for diagnostic confirmation and prenatal screening of ALS. Knowledge of the identity and function of additional ALS causing genes will clarify the molecular mechanism by which these mutated genes cause motor neurons to die during the course of the disease. An understanding of these mechanisms will suggest fruitful approaches toward treatment or prevention of the disease.